Ingredients & integrity


Contamination and counterfeits present a real and growing threat to pharmaceutical companies. Philip Payne, RSSL Pharma business development manager, discusses how working with a contract lab can prevent a major product recall or worse disaster

Contamination and counterfeits present a real and growing threat to pharmaceutical companies. Philip Payne, RSSL Pharma business development manager, discusses how working with a contract lab can prevent a major product recall or worse disaster.

There are many factors that have to be carefully controlled during the manufacture of any pharmaceutical product. However, prime among all of these is the quality of the starting ingredients, not just the active pharmaceutical ingredient (API), but also of the inert, inexpensive and largely uninteresting excipients. This may be stating the obvious, but there have been enough recent examples of problems to warrant remaking the point. It never hurts to be reminded of the potential for contaminated and counterfeit ingredients entering the supply chain.

Reference to the US FDA website reveals several recent warning letters issued to pharmaceutical and ingredient manufacturers over failure to comply with cGMP. The UK's MHRA website similarly publishes recalls due to cGMP failings found during inspection of contract manufacturers.

contamination issues

The take-home message is that despite the careful regulation of pharmaceutical manu-facturing and the universal understanding that cleanliness, hygiene and cGMP are all- important, failings do still occur that lead to contamination, be it chemical or micro-biological. There is no reason to suppose that suppliers of ingredients are immune to the same kind of failings.

Indeed, readers may recall the deaths that occurred in 2008 after contaminated heparin was distributed in the US. In this case, the contaminant trail led back, via at least one intermediary, to Changzhou SPL Company of China, which had supplied heparin (derived from porcine sources) contaminated with oversulfated chondroitin sulfate (OSCS).

supply chain control

On the excipient side, readers may also recall several separate incidents of products, such as cough mixtures and toothpastes, which have contained glycerin contaminated with diethylene glycol (DEG). Over a period of many years there have been several deaths worldwide as a consequence of this repeated contamination. In July 2009, the US Pharmacopoeia initiated revisions to the monographs of four pharmaceutical excipients (propylene glycol, sorbitol solution, sorbitol sorbitan solution and noncrystallising sorbitol solution) in light of hazards associated with DEG contamination.

These are the cases for which there has been widespread publicity. Individual companies will no doubt know of instances kept out of the public domain where ingredients have been found to be out of specification even when accompanied by a certificate of compliance.

The problem of ensuring the quality of supplies is somewhat complicated by the complexity of the modern supply chain. It is hard enough to verify the bona fides of direct suppliers, but even more difficult to exercise any control over the suppliers to the suppliers, and so on to the furthest reaches of the supply chain. This is a genuine concern when more and more APIs and excipients are being sourced from countries with a relatively short history of regulation and less familiarity with the application of cGMP and GDP.

There have been well-documented problems with supplies of pharmaceuticals and ingredients from emerging economies. Examples range from the careless to the criminal, and the US FDA has initiated special measures to help some countries to meet the standards demanded by cGMP. That is not to characterise the whole of the developing world as a source of poor products; however, it should act as a reminder that the purity of product and ingredients cannot be taken for granted, and every supplier must be required to prove their bona fides and product quality, regardless of where they are based.

The fact is that vulnerabilities exist at every point, not least in transit, where any lack of control during warehousing and distribution may undermine all of the control exercised during manufacture. Inspectors frequently cite inadequate control of temperature, for example, as a failure of Good Distribution Practice (GDP), and a reason for supplies failing to meet their specification.

Sadly, vulnerabilities in the supply chain also offer a route for counterfeit supplies to enter the legitimate market. Therefore, pharmaceutical manufacturers need to be aware not only of the potential for their own products to be counterfeited, but also of the risk of unwittingly purchasing counterfeit ingredients, or ingredients with falsified documentation.

detecting the problems

The most certain assurance that any pharmaceutical producer can have concerning the quality of its supplies is to adopt a routine programme of testing in support of regular inspections and audits of suppliers. Any out of specification (OOS) results should always be investigated further. It may even be sensible to investigate results within specification if there is a perceivable trend towards an OOS scenario.

One recent incident investigated by the laboratories at RSSL Pharma, on behalf of a pharmaceutical manufacturer, nicely illustrates this point. An ingredient was testing as a borderline OOS case, which was unusual from a historical perspective. It would have been possible merely to accept the test result as "within specification", but further investigation was sanctioned.

Further analysis and an inspection of the supplier revealed that it had changed both its manufacturing process, and more critically, the supplier of one of its own ingredients, without informing its customer. As a consequence, the supplied ingredient no longer conformed to either GMP or the technical agreement that was in place, albeit that it came from a "legitimate" source and was within specification.

This example harks back to the earlier observation that it is almost impossible to exercise control over ingredient supplies beyond the initial supplier, yet it is with their suppliers, and the suppliers to their suppliers that problems may be introduced.

When one considers the heparin example given above, one cannot conceive of a drug manufacturer in the US or UK having any control over the pig farmers in China, or perhaps the suppliers of their animal feed (remember BSE and the impact it had on the use of gelatin), who were at the starting point of this particular supply chain.

Yet, as a different example from the food industry has shown, contamination of supplies at the very earliest stage (melamine added to milk that ultimately went into infant formula preparations), often have the potential to cause the most damage.

There is a problem, of course, in predicting what manner of contamination it is sensible to try to detect by routine testing. Screening for heavy metals, known degradation products and solvent residues is common and worthwhile. But before the contamination came to light, who would have thought to check specifically for DEG in glycerin, or OSCS in heparin?

That said, an analysis designed to assay the purity of an ingredient will, almost certainly, highlight the presence of any impurity. It is then down to the skill of the chemists to determine what the impurity is, how it got there, and what kind of threat it represents.

This kind of emergency investigation may require multi-disciplinary expertise not available to every laboratory, especially the laboratory that expects to handle only routine assays.

It is for this reason that many licence holders and their manufacturers elect to partner with a contract laboratory that can provide the extra expertise if required. Some prefer to contract out even the routine assay, but in either event, when contamination is suggested by the original analysis, the first step is to confirm the test result.

out of spec investigations

Repeating the test is essential to rule out laboratory error as a possible explanation for the contamination. Assuming that the OOS result is genuine, the emergency investigation must then find out what has gone wrong.

In some cases, it may be possible to identify the contaminant directly using GC-Mass Spectrometry (GC-MS). This is a technique that involves separation of the chemical constituents of the product according to their volatility, and identifies specific compounds according to their molecular weight and the molecular weight of their ion fragments.

There are other chemical techniques that might be used. Nuclear Magnetic Resonance (NMR) excels in the identification of metabolites or drug degradation products. It can also be used for impurity profiling and, increasingly, has a crucial role to play in the detection and identification of counterfeit drug products. Optical isomers are a particular class of contaminant that can be of critical importance and NMR provides a means for determining optical purity with detection limits in some cases of less than 0.1%.

It is useful to have a full production history of the suspect sample, and a control sample against which it can be compared. The size, shape and position (retention time) of the contaminant peaks on a High Pressure Liquid Chromatography (HPLC) chromatogram may reveal some information about the contaminant. Where UV detection is used, it may be possible to use the retention time and UV data together to produce a "shortlist" of potential contaminant identities. The candidate compounds can then be sourced and their HPLC retention times cross-referenced.

This may be easier said than done, since it is not necessarily the case that the contaminating chemical is commercially available. Indeed, the contaminant may only ever be produced in the specific circumstances that have given rise to its presence in this particular instance, making identification a much greater challenge.

While it may not be possible to prevent contamination of ingredients, or to be 100% sure of the integrity of the supply chain, it is always possible to investigate an OOS situation. The information acquired by such an investigation will usually offer an explanation as to how the incident occurred and how it should be addressed.

Such data is vital in assisting the manufacturer to decide what measures need to be introduced to prevent a recurrence, and to implement checks and procedures that will help to maintain the integrity of the supply chain in future.